This chapter reconceptualizes the everyday built environment as a dynamic “indoor pathosphere”—a biologically active system in which airborne viruses, bacteria, and fungi are continuously generated, transported, transformed, and removed through physical, chemical, and architectural processes. Moving beyond the traditional droplet–airborne dichotomy, it synthesizes evidence from aerosol physics, building science, microbiology, and public health to demonstrate that respiratory infection is fundamentally an environmental and engineering phenomenon as much as a biomedical one. The chapter explains how evaporation, humidity, airflow, and human thermal plumes convert exhaled droplets into persistent aerosols, enabling both short-range and long-range airborne transmission even in spaces that meet conventional ventilation standards. It critically evaluates the historical overemphasis on surface disinfection and clarifies the limited role of fomites in everyday settings relative to shared air, while acknowledging material persistence and re-aerosolization as secondary pathways. The thermodynamic envelope of buildings—particularly relative humidity and temperature—is shown to exert strong control over viral viability, aerosol lifetime, and host susceptibility, establishing indoor climate management as a core infection-control strategy. The chapter further extends the analysis to bacterial and fungal bioaerosols, plumbing-generated aerosols, and wastewater surveillance, highlighting the poly-microbial nature of indoor risk. Engineering controls are examined as a hierarchical “mechanical immune system” comprising ventilation, high-efficiency filtration, ultraviolet germicidal irradiation, and cautious use of chemical disinfectants, supported by source control measures such as masking and adaptive building policies. Quantitative risk modeling using the quanta concept and the Wells–Riley framework is integrated with emerging sensor-based approaches, particularly CO2 monitoring, to operationalize real-time risk management. Finally, the chapter situates infection-resilient design within economic, ethical, and policy contexts, arguing that clean indoor air should be treated as a public good and a fundamental component of healthy, equitable, and future-ready buildings.